Open AccessSmall‐molecule peptides inhibit Z α 1 ‐antitrypsin polymerization
Author(s) -
Chang YiPin,
Mahadeva Ravi,
Chang WunShaing W.,
Lin ShengChieh,
Chu YenHo
Publication year - 2009
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2008.00608.x
Subject(s) - peptide , tetrapeptide , chemistry , polymerization , biochemistry , polymer , organic chemistry
The Z variant of α 1 ‐antitrypsin (AT) polymerizes within the liver and gives rise to liver cirrhosis and the associated plasma deficiency leads to emphysema. In this work, a combinatorial approach based on the inhibitory mechanism of α 1 ‐AT was developed to arrest its pathogenic polymerization. One peptide, Ac‐TTAI‐NH 2 , emerged as the most tight‐binding ligand for Z α 1 ‐AT. Characterization of this tetrapeptide by gel electrophoresis and biosensor analysis revealed its markedly improved binding specificity and affinity compared with all previously reported peptide inhibitors. In addition, the peptide is not cytotoxic to lung cell lines. A model of the peptide‐protein complex suggests that the peptide interacts with nearby residues by hydrogen bonds, hydrophobic interactions, and cavity‐filling stabilization. The combinatorially selected peptide not only effectively blocks the polymerization but also promotes dissociation of the oligomerized α 1 ‐AT. These results are a significant step towards the potential treatment of Z α 1 ‐AT related diseases.